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Updated: Apr 3, 2026
Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
Published on: March 10, 2017
The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant
Sheng Guo1, Chengying Yang1, Bo Diao1
1Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
Abstract:
Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Whereas, the viral infection in IL-1β receptor-I deficient (IL-1R1-/-) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45+Gr-1high neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1β induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1β axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases.
Insights
Excessive inflammation from viral hepatitis causes severe liver disease. Targeting the ROS/NLRP3/IL-1β pathway reduces inflammation and mortality in viral fulminant hepatitis models.
Area of Science:
- Hepatology
- Immunology
- Virology
Background:
- Viral fulminant hepatitis (FH) is a severe liver disease with high mortality.
- Current treatments are limited by incomplete understanding of inflammatory pathogenesis in viral hepatitis.
Purpose of the Study:
- To elucidate the inflammatory mechanisms driving viral FH.
- To identify potential therapeutic targets for viral FH and related inflammatory diseases.
Main Methods:
- Utilized a murine hepatitis virus strain-3 (MHV-3) mouse model for viral FH.
- Investigated the roles of IL-1β, IL-1R1, ROS, NLRP3 inflammasome, and Caspase-1 in disease pathogenesis.
- Employed gene-deficient mice (IL-1R1-/-, p47phox-/-, NLRP3-/-, Caspase-1-/-) and IL-1Ra treatment.
Main Results:
- MHV-3 infection elevated IL-1β, leading to severe hepatitis and mortality.
- Mice deficient in IL-1R1 or treated with IL-1Ra showed reduced viral replication, disease severity, and mortality.
- The ROS/NLRP3/IL-1β axis was identified as a key pathway driving severe liver inflammation and FH.
Conclusions:
- The ROS/NLRP3/IL-1β signaling pathway is critically involved in the pathogenesis of viral FH.
- Targeting this axis offers a promising strategy for developing effective treatments for viral FH and other severe inflammatory conditions.
